Application of a pharmacokinetic/pharmacogenetic approach to assess the nicotine metabolic profile of smokers in the real-life setting

The nicotine metabolite ratio, i.e., the ratio 3-hydroxycotinine/cotinine, is used to assess the nicotine metabolic status and has been proven to predict the response to smoking cessation treatments in randomized clinical trials. In the current study, a pharmacokinetic-pharmacogenetic integrated approach is described, based on the development of a liquid chromatography–tandem mass spectrometry (LC/MS/MS) method for nicotine metabolite ratio assay in plasma and a real-time PCR analysis for fast genotyping of CYP2A6. The pharmacokinetic-pharmacogenetic approach was validated in 66 subjects with different smoking status. The LC/MS/MS assay was rapid and sensitive enough to detect plasma cotinine levels also in second-hand exposed abstainers. In the cohort of patients of the present study the following results were obtained: (i) the frequencies of CYP2A6 genetic variants were comparable with those from clinical trials carried out in Caucasian populations; (ii) all the subjects carrying the CYP2A6 deficient allele also had a slow metabolizer phenotype; (iii) slow metabolizers had mean nicotine metabolite ratio approximately 50% of that of the normal/fast metabolizers; (iv) women had higher nicotine metabolite ratio than men; and (v) salivary nicotine metabolite ratio measures were comparable to plasma levels. Overall, the findings of the current study demonstrate that the simultaneous assessment of nicotine metabolite ratio and CYP2A6 genotype from human blood samples is feasible and accurate and could be used in a smoking cessation program to optimize treatments and identify those smokers who inherit metabolically deficient CYP2A6 alleles

Faster Onset of Bronchodilation with Formoterol than with Salmeterol in Patients with Stable, Moderate-Severe Copd: Results of a Randomized, Double-Blind Clinical Study

OBJECTIVES: To compare the onset and magnitude of bronchodilation after dry powder inhalations of formoterol fumarate (Foradil Aerolizer) versus salmeterol xinofoate (Serevent Diskus) with respect to normalized (*) forced expiratory volume in 1 s area under the curve 0 to 1 h after inhalation (FEV1AUC*0-1 h).DESIGN: A double-blind, double-dummy, multicentre, randomized, placebo controlled, single-dose, five-period crossover study.SETTING: Five centres in four countries -- one centre each in France, Greece and Italy, and two centres in the Netherlands.PATIENTS: Forty-seven patients aged 42 to 80 years (mean age 63.5 years) with chronic obstructive pulmonary disease (COPD) stage II and III, and mean baseline FEV11.17 L (range 0.56 to 1.77 L).INTERVENTIONS: Patients inhaled single doses of formoterol dry powder (12 and 24 μg), single doses of salmeterol (50 and 100 μg) and matching placebo on five separate days.MAIN RESULTS: The estimates of treatment difference in absolute terms (0.086 L) and percentage change from predose baseline (7.8%) for the primary end point, FEV1AUC*0-1 h, showed that formoterol 12 μg was statistically significantly superior to salmeterol 50 μg (P=0.0044 and P=0.0021, respectively). In addition, both doses of formoterol were statistically superior to placebo for both absolute improvement and percentage change (P=0.0001). The analysis of secondary variables also confirmed the superiority of formoterol over salmeterol.CONCLUSIONS: Formoterol is associated with a faster onset of bronchodilation than salmeterol in patients with COPD

Air pollution and lung function among susceptible adult subjects: a panel study

BACKGROUND: Adverse health effects at relatively low levels of ambient air pollution have consistently been reported in the last years. We conducted a time-series panel study of subjects with chronic obstructive pulmonary disease (COPD), asthma, and ischemic heart disease (IHD) to evaluate whether daily levels of air pollutants have a measurable impact on the lung function of adult subjects with pre-existing lung or heart diseases. METHODS: Twenty-nine patients with COPD, asthma, or IHD underwent repeated lung function tests by supervised spirometry in two one-month surveys. Daily samples of coarse (PM(10–2.5)) and fine (PM(2.5)) particulate matter were collected by means of dichotomous samplers, and the dust was gravimetrically analyzed. The particulate content of selected metals (cadmium, chrome, iron, nickel, lead, platinum, vanadium, and zinc) was determined by atomic absorption spectrometry. Ambient concentrations of nitrogen dioxide (NO(2)), carbon monoxide (CO), ozone (O(3)), and sulphur dioxide (SO(2)) were obtained from the regional air-quality monitoring network. The relationships between concentrations of air pollutants and lung function parameters were analyzed by generalized estimating equations (GEE) for panel data. RESULTS: Decrements in lung function indices (FVC and/or FEV(1)) associated with increasing concentrations of PM(2.5), NO(2 )and some metals (especially zinc and iron) were observed in COPD cases. Among the asthmatics, NO(2 )was associated with a decrease in FEV(1). No association between average ambient concentrations of any air pollutant and lung function was observed among IHD cases. CONCLUSION: This study suggests that the short-term negative impact of exposure to air pollutants on respiratory volume and flow is limited to individuals with already impaired respiratory function. The fine fraction of ambient PM seems responsible for the observed effects among COPD cases, with zinc and iron having a potential role via oxidative stress. The respiratory function of the relatively young and mild asthmatics included in this study seems to worsen when ambient levels of NO(2 )increase

Respiratory symptoms in children living near busy roads and their relationship to vehicular traffic: results of an Italian multicenter study (SIDRIA 2)

BACKGROUND: Epidemiological studies have provided evidence that exposure to vehicular traffic increases the prevalence of respiratory symptoms and may exacerbate pre-existing asthma in children. Self-reported exposure to road traffic has been questioned as a reliable measurement of exposure to air pollutants. The aim of this study was to investigate whether there were specific effects of cars and trucks traffic on current asthma symptoms (i.e. wheezing) and cough or phlegm, and to examine the validity of self-reported traffic exposure. METHODS: The survey was conducted in 2002 in 12 centers in Northern, Center and Southern Italy, different in size, climate, latitude and level of urbanization. Standardized questionnaires filled in by parents were used to collect information on health outcomes and exposure to traffic among 33,632 6-7 and 13-14 years old children and adolescents. Three questions on traffic exposure were asked: the traffic in the zone of residence, the frequency of truck and of car traffic in the street of residence. The presence of a possible response bias for the self-reported traffic was evaluated using external validation (comparison with measurements of traffic flow in the city of Turin) and internal validations (matching by census block, in the cities of Turin, Milan and Rome). RESULTS: Overall traffic density was weakly associated with asthma symptoms but there was a stronger association with cough or phlegm (high traffic density OR = 1.24; 95% CI: 1.04, 1.49). Car and truck traffic were independently associated with cough or phlegm. The results of the external validation did not support the existence of a reporting bias for the observed associations, for all the self-reported traffic indicators examined. The internal validations showed that the observed association between traffic density in the zone of residence and respiratory symptoms did not appear to be explained by an over reporting of traffic by parents of symptomatic subjects. CONCLUSION: Children living in zones with intense traffic are at higher risk for respiratory effects. Since population characteristics are specific, the results of validation of studies on self-reported traffic exposure can not be generalized

Covid-19 and the role of smoking: the protocol of the multicentric prospective study COSMO-IT (COvid19 and SMOking in ITaly).

The emergency caused by Covid-19 pandemic raised interest in studying lifestyles and comorbidities as important determinants of poor Covid-19 prognosis. Data on tobacco smoking, alcohol consumption and obesity are still limited, while no data are available on the role of e-cigarettes and heated tobacco products (HTP). To clarify the role of tobacco smoking and other lifestyle habits on COVID-19 severity and progression, we designed a longitudinal observational study titled COvid19 and SMOking in ITaly (COSMO-IT). About 30 Italian hospitals in North, Centre and South of Italy joined the study. Its main aims are: 1) to quantify the role of tobacco smoking and smoking cessation on the severity and progression of COVID-19 in hospitalized patients; 2) to compare smoking prevalence and severity of the disease in relation to smoking in hospitalized COVID-19 patients versus patients treated at home; 3) to quantify the association between other lifestyle factors, such as e-cigarette and HTP use, alcohol and obesity and the risk of unfavourable COVID-19 outcomes. Socio-demographic, lifestyle and medical history information will be gathered for around 3000 hospitalized and 700-1000 home-isolated, laboratory-confirmed, COVID-19 patients. Given the current absence of a vaccine against SARS-COV-2 and the lack of a specific treatment for -COVID-19, prevention strategies are of extreme importance. This project, designed to highly contribute to the international scientific debate on the role of avoidable lifestyle habits on COVID-19 severity, will provide valuable epidemiological data in order to support important recommendations to prevent COVID-19 incidence, progression and mortality

Reference values for pulmonary function test: suggestions for a correct use and interpretation

This paper describes the complex reasoning activity the respiratory clinician performs while using the respiratory function tests for diagnosing a disease. The probability each functional parameter is belonging to a healthy subject is the first useful measure to start with that reasoning. In a second step, a set of parameters is evaluated to define a functional syndrome and, finally, the identification of the disease underlying that syndrome is the last step of this journey. The comparison of measured parameters with reference data in healthy subjects is crucial to measure the probability at the beginning of the diagnostic reasoning. Reference data are often used also to define the severity of a respiratory disease or to evaluate the efficacy of a therapeutic intervention. Clearly, reference data are used to address quite different tasks, the methodological implications of which are discussed in this paper. In the last part of this paper the authors present their suggestions and some temporary solutions to what is a lack of knowledge for a more sensible utilization of respiratory reference values

Strategies and dismantling solutions for RPV internals of Trino NPP

The last step of nuclear power plants’ life is the decommissioning phase. Many strategies have been developed in the last decades; the main options consists in: immediate dismantling, safe storage and entombment. In Italy, due to the premature shutdown of nuclear power plants (NPP) as a consequence of the 1986 referendum following the Chernobyl accident, all the NPPs were shut down. Therefore, currently decommissioning activities are under way. In this work specifically the dismantling procedures of the “Enrico Fermi” NPP reactor pressure vessel (RPV) are dealt with. The attention is so focused on the optimization of number, position and length of the Internals cuts, optimization of volume and number of waste containers, and of the dose rates, according to the imposed site and the transport requirements. The systematic approach developed to identify the optimum dismantling solution is presented and discussed. To the intent three solutions have been identified as more advantageous. In addition, the evaluation of dose rate outside the container has been performed by means of VISIPLAN software, in order to guarantee the respect of the limits imposed by National and International regulations. The obtained results suggest that the cutting of Zircalloy elements in correspondence of the gap between two non-consecutive central stumps, with the possibility to re-arrange the element, led to a significant reduction of the number of containers, with consequent decrease of the stowed RWs volume and overall supplying costs of the activity

Chronic obstructive pulmonary disease: moving from symptom relief to mortality reduction

Chronic obstructive pulmonary disease (COPD) has a 3-year mortality rate up to 37%, 2–6 times higher than the general population. We present evidence supporting pharmacological therapies to improve patient life expectancy, focusing on inhaled corticosteroids (ICSs) combined with long-acting bronchodilators (LABDs). A reduction in 3-year all-cause mortality (ACM) has been shown in patients with severe COPD treated with fluticasone propionate (an ICS) and salmeterol [long-acting beta-agonist (LABA)], compared with placebo. An observational study of elderly patients with severe COPD and multiple comorbidities suggested ICS+LABD reduce ACM compared with LABD monotherapy. Patients with symptomatic COPD at risk of exacerbations saw a mortality benefit with the ICS/long-acting muscarinic antagonist (LAMA)/LABA combinations fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) or budesonide/glycopyrrolate/formoterol (BUD/GLY/FOR) versus UMEC/VI or GLY/FOR (LAMA/LABA combinations) in the IMPACT and ETHOS trials, respectively. Reduced risk of mortality may be due to modulation of airway inflammation, thereby reducing activation of proinflammatory mediators in the peripheral circulation. Importantly, estimated annual risk reduction for ACM with ICS/LAMA/LABA combinations in patients with COPD is of the same order of magnitude as for statins (patients with coronary disease) and angiotensin-converting enzyme inhibitors (patients with vascular disease). Based on the current data, the pharmacological treatment of COPD appears not only able to improve symptoms and reduce the frequency of exacerbations but is also very promising in improving patient prognosis in the long term

Handling and Conditioning Techniques of Activated Swarfs for the Decommissioning of the E. Fermi Nuclear Power Plant

In this paper, a new technique to handle solid radioactive materials inside a liquid matrix is presented. The conceptual design of the device profits of the experience and know-how gained in decontamination procedures. The proposed system makes use of an ejector for the suction of a water-highly radioactive swarf mixture from the purifier pool of the Italian E. Fermi nuclear power plant (NPP) and moving it in a suitable container for the subsequent conditioning. A dedicated circuit with an ejector to demonstrate the feasibility of the method was realized. A minimum inlet flow rate was found to have swarf suction. The feasibility of the method was demonstrated, even if it is required to homogenize the inlet mixture to avoid swarf packing conditions inside the ejector